The goal of this proposal is to examine morphological and neurochemical correlates of prior chronic cocaine self- administration in rats. Due to its role in drug reward, the proposed experiments will focus on the nucleus accumbens (Nac), and, in particular, the interaction of NAc acetylcholine (ACh) with both GABA and glutamate mechanisms. Various cocaine administrations cause facilitation of NAC Ach and glutamate activity and reduction in GABAergic function following exposure. Evidence also exists for functional connectivity between NAc ACh and both GABA and glutamate. The overall hypothesis for this proposal is that prior cocaine self administration will alter the connectivity between NAc ACh and both GABA and glutamate substrates. The proposed experiments will address this hypothesis by assessing the effect of cocaine self administration on a)the functional responsivity of NAc ACh to local infusion of GABA and glutamate agents, and b) synaptic GABA and glutamate content and morphology in the NAc. The functional component will be assessed by in vivo microdialysis and the synaptic morphology will be examined by quantitative ultrastructural immunocytochemistry in rats following 14 days of self administration. The ability to utilize morphological data to interpret in vivo results as a unique assets of this research. This experiments will provide valuable information on the relationship between key presynaptic structural and postsynaptic functional components of NAc intraneuronal circuitry and the effect of cocaine self-administration on this relationship. Insights on neural substrates that underlie the development of drug sensitization, tolerance, or motivational aspects of stimulant withdrawal may also be gained.